Lavendamycin (A) was isolated from the fermentation broth of Streptomyces lavendulae by Doyle and co-workers. See Doyle et al., Tetrahedron Letters, 22, 4595 (1981) and Gould et al., Fortschr. Chem. Org. Naturst., 41, 77 (1982). Lavendamycin has broad spectrum antitumor, antibacterial and antiviral activity. See, e.g., Shibata et al., J. Antibiot., 33, 1231 (1980); Balitz et al., J. Antibiot., 35, 259 (1982); Boger et al., J. Med. Chem., 30, 1918 (1987).
Lavendamycin methyl ester (B) is also known. It can be prepared by esterification of lavendamycin. Doyle et al., Tetrahedron Letters, 22, 4595 (1981). The first total synthesis of lavendamycin methyl ester was reported by Kende and Ebetino in 1984. See Kende et al., Tetrahedron Letters, 25, 923 (1984) and Kende et al., Heterocycles, 21, 91 (1984). They accomplished the synthesis of lavendamycin methyl ester through a Bischler-Napieralski condensation of a substituted quinaldic acid with .beta.-methyltryptophan methyl ester followed by cyclization and functionalization of the A ring. Boger and his co-workers have synthesized lavendamycin methyl ester by a Friedlander condensation of a functionalized aminoaldehyde with a .beta.-carboline followed by other transformations. Boger et al., J. Org. Chem., 50, 5790 (1985). Formal syntheses of lavendamycin methyl ester have been reported in Hibino et al., Heterocycles, 23, 261 (1985) and Rao et al., Tetrahedron, 42, 5065 (1986). For a recent review of lavendamycin syntheses, see Rao, in Recent Progress In Chemical Synthesis Of Antibiotics, 497-531 (Lukacs et al. eds., 1990).
Hibino's group has reported the synthesis of demethyllavendamycin methyl ester (C) in Hibino et al., Heterocycles, 20, 1957 (1983). Hibino's group synthesized demethyllavendamycin methyl ester by a Pictet-Spengler type cyclization of 8-benzyloxyquinoline-2-aldehyde with tryptophan methyl ester, followed by aromatization and hydrogenation to give an 8-hydroxyquinoline intermediate. This intermediate was brominated to give the 5,7-dibromo-8-hydroxyquinoline. Oxidation of the 5,7-dibromo-8-hydroxyquinoline yielded the 7-bromoquinolinequinone, and replacement of the bromine with sodium azide, followed by reduction of the azide with sodium hydrosulfite, yielded demethyllavendamycin methyl ester.
This synthetic scheme based on a Pictet-Spengler type cyclization was also used by Hibino's group for the formal synthesis of lavendamycin methyl ester mentioned above. Hibino et al. indicate that lavendamycin ethyl ester can be prepared using this same synthetic scheme. See Hibino et al., Heterocycles, 23,261 (1985).
The Pictet-Spengler cyclization approach has further been used by Hibino's group to synthesize desaminodesmethyllavendamycin methyl ester (D) and eight other lavendamycin analogs. See Hibino et al., Chem. Pharm. Bull., 34, 1376 (1986). This article reports that the relative mutagenic potency of the lavendamycin analogs was drastically influenced by the nature of the substituent (e.g., methyl and/or bromine) and that lavendamycin analogs having a methyl group at the 3' position were more mutagenic.
The structures of lavendamycin and analogs B-D are presented below: ##STR2##
During preliminary work aimed at the total synthesis of lavendamycin, Rao et al. synthesized two additional analogs (E) and (F) of lavendamycin. See Rao et al., Indian J. Chem., 23B, 496 (1984). The structures of lavendamycin analogs E-F are presented below: ##STR3##
Lavendamycin is similar structurally to streptonigrin (G). Streptonigrin also has a broad spectrum of antitumor, antibacterial and antiviral activity. Balitz et al., J. Antibiot., 35, 259 (1982); Rao et al., J. Am. Chem. Soc., 85, 2532 (1986); Boger et al., J. Med. Chem., 30, 1918 (1987). With notable exceptions, lavendamycin has been found to be comparable to, although less potent than, streptonigrin in its observed spectrum of activity. Id.; Balitz et al., J. Antibiot., 35, 259 (1982). The structure of streptonigrin is presented below: ##STR4##
Streptonigrin and several streptonigrin derivatives have been synthesized. See Driscoll et al., Cancer Chemother. Rep. (Part 2), 4, 1 (1974) (four streptonigrin derivatives and 1500 quinones including several quinolinequinone analogs of streptonigrin having various substituents at positions 2, 6 and 7); Rao, Cancer Chemother. Rep. (Part 2), 4, 11 (1974) (streptonigrin derivatives and AB and ABC ring analogs thereof); Kende et al., Tetrahedron Lett., 4775 (1978) (tetracyclic aminoquinone possessing full streptonigrin carbon skeleton but with different substituents on the C and D rings); Basha et al., J. Am. Chem. Soc., 102, 3962 (1980) (streptonigrin); Kende et al., J. Am. Chem. Soc., 103, 1271 (1981) (streptonigrin); Weinreb et al., J. Am. Chem. Soc., 104, 536-44 (1982) (streptonigrin); Panek et al., Diss. Abs. Int'l, 46, 1176B (1985) (streptonigrin); Miyasaka et al., J. Chem. Soc. Perkin Trans., 1, 479 (1986) (streptonigrin 2'-amide derivatives; also mentions a 7-position amide obtained by high-yield microbial synthesis of Streptomyces griseus); Tolstikov et al., J. Antibiot., 45, 1020 (1992) (2'-amide, aminodicarboxylic acid and amino sugar derivatives of streptonigrin); Tolstikov et al., J. Antibiot., 45, 1002 (1992) (2'-decarboxy-2'-amino streptonigrin); Preobrazhenskaya et al., J. Antibiot., 45, 227 (1992) (streptonigrone from streptonigrin, streptonigrin and streptonigrone 8'-alkyl ethers, and other streptonigrin and streptonigrone derivatives); U.S. Pat. No. 3,372,090 (ester, 2'-amide, 2'-hydrazide, ether, dihydro, desamino and acetyl (O-acetyl, N-acetyl, tetraacetyl) derivatives of streptonigrin); U.S. Pat. No. 3,804,947 (isopropylidene azastreptonigrin, streptonigrin monoxime and esters and other derivatives thereof); and JP 61-280490 (streptonigrin 2'-amides).
The biological activities of several 2'-position streptonigrin derivatives have been studied. The derivatives include 2'-esters, 2'-amides, 2'-hydrazides, and 2-'amino acid derivatives. The effects of the substituents on the biological activity of streptonigrin varied depending on the substituent and the type of activity being studied. See Rivers et al., Cancer Chemotherapy Rep., 46, 17 (1965); Harris et al., Cancer, 18, 49 (1965); Kremer et al., Biochem. Pharmacol., 15, 1111 (1966); Kaung et al., Cancer, 23, 1280 (1969); Inouye et al., J. Antibiot,, 38, 1429 (1985); Okada et al., J. Antibiot., 39, 306 (1986); Inouye et al., J. Antibiot., 39, 550 (1986); Okada et al., J. Antibiot., 40, 230 (1987); Take et al., J. Antibiot., 42, 968 (1989); Tolstikov et al., J. Antibiot., 45, 1020 (1992).
The biological properties of streptonigrin, streptonigrin methyl ester and isopropylidene azastreptonigrin have been compared. See Kremer et al., Cancer Chemother. Rep., 51, 19 (1967); Mizuno, Biochem. Pharmacol., 16, 933 (1967); Chaube et al., Cancer Chemother. Rep. (Part 1), 53, 23 (1969) and Chirigos et al., Cancer Chemother. Rep. (Part 1), 57, 305 (1973). Again, the effects of the substituents varied depending on the activity being investigated.
The antibacterial activity of streptonigrin, streptonigrin methyl ester and streptonigrin 8'-alkyl ethers has been studied. See Preobrazhenskaya et al., J. Antibiot., 45, 227 (1992). The 8'-alkyl ethers exhibited slightly greater antibacterial activity than streptonigrin methyl ester, but less than streptonigrin.
A naturally-occurring analog of streptonigrin, 10'-desmethoxystreptonigrin, has been discovered. U.S. Pat. No. 5,158,960; Liu et al., J. Antibiot., 45, 454-57 (1992). In addition to 10'-desmethoxystreptonigrin, U.S. Pat. No. 5,158,960 discloses salts, esters and amides of 10'-desmethoxystreptonigrin. Exemplary esters and amides are those prepared by esterifying the 2'-carboxyl or by forming an amide group at the 2'-position. 10'-Desmethoxystreptonigrin was found to have anticancer and antimicrobial, particularly broad spectrum antibacterial, activity. U.S. Pat. No. 5,158,960; Liu et al., J. Antibiot., 45, 454-57 (1992). It was also found to be three times more active than streptonigrin in an assay for the inhibition of the farnesylation of ras oncogene p21 protein. Id. U.S. Pat. No. 5,158,960 teaches that, since 10'-desmethoxystreptonigrin inhibits the farnesylation of ras oncogene p21 protein, it may be expected to block the neoplastic effect of ras oncogenes in tumor cells.
EP application 185,979 discloses another naturally-occurring streptonigrin analog which has a hydroxyl group in place of the methoxy group at the 6-position of streptonigrin. This compound is reported to exhibit only slightly less antitumor activity than streptonigrin, but to exhibit much lower cytotoxicity. This EP application also discloses derivatives synthesized by making use of the 6-position hydroxyl.
A third naturally-occurring analog of streptonigrin is streptonigrone. Herlt et al., J. Antibiot., 38, 516 (1985). Streptonigrone has also been synthesized from streptonigrin, and streptonigrone 8'-alkyl ethers and other streptonigrone derivatives have been prepared. Preobrazhenskaya et al., J. Antibiot., 45, 227 (1992). Also, 2'-decarboxy-2'-aminostreptonigrin, considered to be an analog of streptonigrone, has been synthesized. Tolstikov et al., J. Antibiot., 45, 1002 (1992). Streptonigrone and its derivatives have generally been found to be inactive or much less active than streptonigrin. See Herlt et al., J. Antibiot., 38, 516 (1985); Preobrazhenskaya et al., J. Antibiot., 45, 227 (1992); Tolstikov et al., J. Antibiot., 45, 1002 (1992).
Finally, a number of streptonigrin and lavendamycin partial structures have been synthesized and their biological activities studied in an attempt to determine the minimum potent pharmacophore of streptonigrin and lavendamycin. See Driscoll et al., Cancer Chemother. Rep. (Part 2), 4, 1 (1974) (1500 quinones including several quinolinequinone analogs of streptonigrin having various substituents at positions 2, 6 and 7; also four streptonigrin derivatives); Rao, Cancer Chemother. Rep. (Part 2), 4, 11 (1974) (streptonigrin derivatives and AB and ABC ring analogs thereof); Rao, J. Heterocyclic Chem., 12, 725 (1975) (2-phenyl- and 2,2-pyridyl-quinoline-5,8-diones); Rao, J. Heterocyclic Chem., 14, 653 (1977) (ABC ring portion of streptonigrin and derivatives thereof); Lown et al., Can. J. Chem., 54, 2563 (1976) (2-(o-nitrophenyl)- and 2-(o-aminophenyl)-5,8-quinolinediones); Lown et al., Can. J. Biochem., 54, 446 (1976) (substituted 5,8-quinolinequinones related to streptonigrin); Liao et al., J. Heterocyclic Chem., 13, 1283 (1976) (CD ring portion of streptonigrin); Rao et al., J. Heterocyclic Chem., 16, 1241 (1979) (ABC ring portion of streptonigrin and analogs); Shaikh et al., Diss. Abs. Inter., 44, 1464B (1983) (2,3-disubstituted-1,4-naphthalenediones, 6,7-disubstituted 5,8-quinoline, isoquinoline, quinoxoline, quinazoline, phthalazinediones, and 2-(o-nitrophenyl)-6,7-disubstituted-5,8-quinolinediones related to streptonigrin); Boger et al., J. Org. Chem., 50, 5782 (1985) (AB and CDE ring portions of lavendamycin); Panek et al., Diss. Abs. Inter., 46, 1176B (1985) (streptonigrin and lavendamycin carbon framework); Renault et al., J. Am. Chem. Soc., 104, 1715 (1985) (5,8-quinazolinediones); Shaikh et al., J. Med. Chem., 29, 1329 (1986) (a series of aza and diaza bicyclic quinones related to the AB ring system of streptonigrin); Boger et al., Heterocycles, 24, 1067 (1986) (streptonigrin and lavendamycin AB ring systems); Inouye et al., J. Antibiot., 40, 105 (1987) (6-methoxy-5,8 -dihydroquinoline-5,8-dione and 6-methoxy-7-methyl-5,8-dihydroquinoline-5,8-dione); Boger et al., J. Med. Chem., 30, 1918 (1987) (various streptonigrin and lavendamycin partial structures are discussed, including the AB, ABC, CD and CDE rings and derivatives thereof); Take et al., J. Antibiot., 40, 679 (1987) (quinoline quinones, 7-isoquinoline quinones, indole quinone); Yasuda et al., J. Antibiot., 24, 1253 (1987) (7-amino-2-(2 '-pyridyl) quinoline-5,8-quinone-6'-carboxylic acid); Beach, Diss. Abs. Inter., 49, 3204-B (streptonigrin isoquinoline analogs); Kitahara et al., Chem. Pharm. Bull., 38, 2841 (1990) (8-amino-5,6-quinolinediones); Rao et al., J. Med. Chem., 34, 1871 (1991) (streptonigrin isoquinoline analogs).
Of particular note is Rao, Cancer Chemother. Rep. (Part 2), 4, 11 (1974). This article reports the results of a study of the activity of several streptonigrin derivatives and AB ring analogs which led the author to propose a structure (H) for the minimum potent pharmacophore of streptonigrin. ##STR5## A tricyclic analog of H (corresponding to the ABC rings of streptonigrin) was synthesized and found to be active. Results of interest reported in this article are that replacement of the amine function at position 7 of streptonigrin by OH or OCH.sub.3 led to loss of activity, and streptonigrin derivatives produced by reductive acetylation or methylation of the amine group at position 7 were inactive. Esterification of the carboxyl of streptonigrin with a series of alcohols gave esters which reportedly showed significant activity.
The fully elaborated streptonigrin CD and lavendamycin CDE ring systems, as well as a number of related synthetic structures, have reportedly proved inactive in antimicrobial and cytotoxic assays. Boger et al., J. Med. Chem., 30, 1918 (1987). However, none of the AB and ABC ring analogs of streptonigrin and lavendamycin have been reported to possess cytotoxic, antimicrobial or antitumor activity comparable to streptonigrin. See id.; Driscoll et al., Cancer Chemother. Rep. Part 2, 4, 1 (1974). This suggests a role for the CD rings in the activity of streptonigrin. See Kende et al., Tetrahedron Lett., 48, 4775 (1978).
The following references also describe the synthesis of streptonigrin and lavendamycin partial structures, but do not discuss the activity of the resulting compounds. Liao et al., Angew. Chem, Intern. Edit., 6, 82 (1967) (AB ring portion of streptonigrin); Rao et al., J. Heterocyclic Chem., 12, 731 (1975) (streptonigrin C ring precursors); Liao et al., J. Heterocyclic Chem., 13, 1063 (1976) (the AB ring portion of streptonigrin and the 2-methyl homolog); Hibino et al., J. Org. Chem., 42, 232 (1977) (the AB ring portion of streptonigrin); Wittek et al., J. Org. Chem., 44, 870 (1979) (CD ring portion of streptonigrin); Boger et al., Tetrahedron Lett., 25, 3175 (1984) (the CDE ring portion of lavendamycin); Erickson, Diss. Abs. Inter., 49, 747-B (1988) (4-aminoanthranilic acid, 7-aminoquinaldinic acid, 7-amino-5-hydroxyquinaldinic acid); Molina et al., Tetrahedron Lett., 33, 2891 (1992) (1-substituted-.beta.-carbolines).